Sheffield United have now gone seven games without defeat after ending Reading's run of seven successive games without conceding a goal.
After a goalless first half United manager Neil Warnock told his team to go out and attack in the second half and it paid off.
In the 59th minute defender Jon Harley, on loan from Fulham, scored from close range past Reading's American keeper Marcus Hahnemann.
It was the first goal that Hahnemann had conceded for 749 minutes.
Fourteen minutes from the end he conceded a second. Peter Ndlovu sent over a cross which Dean Windass headed into the Reading net.
It was the last game that Windass will play for United as he comes to the end of a one-month loan spell from Middlesbrough.
Hahnemann was by far the busiest of the two goalkeepers and had to make excellent first-half saves from Phil Jagielka and Michael Tonge.
"We were beaten by a better team,” said Reading manager Alan Pardew. "If we played like we did against Portsmouth the result might have been different.
"But in big games like this you need most of your players to be putting in performances with marks like eight out of ten. We didn't have enough of those and United did."
United boss Neil Warnock said: "I knew their place would be a fortress and I knew how they would play because they always play the same way.
"In the first half I thought we were a bit timid when we got near their goal so at half time I told the lads to have a go. I knew it meant we could end up losing 1-0 but we had to do it."
Pardew added: "I knew the run would end some time, but it is just a shame that it ended in front of 18,000 home supporters."